Subjects: Biology >> Biophysics submitted time 2016-05-15
Duan, Shunlei
Yuan, Guohong
Ren, Ruotong
Xu, Xiuling
Fu, Lina
Li, Ying
Yang, Jiping
Zhang, Weiqi
Liu, Guang-Hui
Liu, Xiaomeng
Li, Jingyi
Tang, Fuchou
Ren, Ruotong
Bai, Ruijun
Liu, Guang-Hui
Ren, Ruotong
Bai, Ruijun
Qu, Jing
Zhang, Weizhou
Wu, Jun
Abstract： PTEN is a tumour suppressor frequently mutated in many types of cancers. Here we show that targeted disruption of PTEN leads to neoplastic transformation of human neural stem cells (NSCs), but not mesenchymal stem cells. PTEN-deficient NSCs display neoplasm-associated metabolic and gene expression profiles and generate intracranial tumours in immunodeficientmice. PTEN is localized to the nucleus in NSCs, binds to the PAX7 promoter through association with cAMP responsive element binding protein 1 (CREB)/CREB binding protein (CBP) and inhibits PAX7 transcription. PTEN deficiency leads to the upregulation of PAX7, which in turn promotes oncogenic transformation of NSCs and instates 'aggressiveness' in human glioblastoma stem cells. In a large clinical database, we find increased PAX7 levels in PTEN-deficient glioblastoma. Furthermore, we identify that mitomycin C selectively triggers apoptosis in NSCs with PTEN deficiency. Together, we uncover a potential mechanism of how PTEN safeguards NSCs, and establish a cellular platform to identify factors involved in NSC transformation, potentially permitting personalized treatment of glioblastoma.
Peer Review Status:
Awaiting Review
Subjects: Biology >> Biophysics submitted time 2016-05-12
Zhang, Weiqi
Wang, Ping
Zhou, Junzhi
Ren, Ruotong
Xu, Xiuling
Yuan, Tingting
Yang, Jiping
Li, Ying
Guan, Dee
Pan, Huize
Duan, Shunlei
Ding, Zhichao
Chen, Chang
Yang, Fuquan
Liu, Guang-Hui
Li, Jingyi
Liu, Xiaomeng
Tang, Fuchou
Suzuki, Keiichiro
Ocampo, Alejandro
Abstract： Werner syndrome (WS) is a premature aging disorder caused by WRN protein deficiency. Here, we report on the generation of a human WS model in human embryonic stem cells (ESCs). Differentiation of WRN-null ESCs to mesenchymal stem cells (MSCs) recapitulates features of premature cellular aging, a global loss of H3K9me3, and changes in heterochromatin architecture. We show that WRN associates with heterochromatin proteins SUV39H1 and HP1 alpha and nuclear lamina-heterochromatin anchoring protein LAP2 beta. Targeted knock-in of catalytically inactive SUV39H1 in wild-type MSCs recapitulates accelerated cellular senescence, resembling WRN-deficient MSCs. Moreover, decrease in WRN and heterochromatin marks are detected in MSCs from older individuals. Our observations uncover a role for WRN in maintaining heterochromatin stability and highlight heterochromatin disorganization as a potential determinant of human aging.
Peer Review Status:Awaiting Review
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